Notch1 hallmarks fibrillary depositions in sporadic Alzheimer's disease.
Notch1 hallmarks fibrillary depositions in sporadic Alzheimer's disease.
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DOI：
10.1186/s40478-016-0327-2
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发表时间：
2016-07-01
影响因子：
7.1
通讯作者：
Alberi L
中科院分区：
文献类型：
--
作者：
Brai E;Alina Raio N;Alberi L
Notch1 信号传导是一种细胞级联反应，在从大脑发育到成人大脑功能的过程中发挥着重要作用。 Notch1 的减少会影响突触可塑性、记忆力和嗅觉。另一方面，脑损伤后 Notch1 过度激活不利于神经元存活。早老素中的一些家族性阿尔茨海默病 (FAD) 突变会影响 Notch1 的加工/激活。其他人报告称，Notch1 在散发性阿尔茨海默病 (AD) 中过度表达。这些工作表明 Notch1 的失衡可能与 AD 病理生理学有关。在这项研究中，我们探讨了 Notch1 改变是否可以被视为 AD 的标志。对死后患者皮质和海马组织上 Notch1 的免疫组织化学分析表明，Notch1 在散发性 AD 受试者脑实质的斑块状结构中积累。进一步分析表明，Notch1 移位与纤维缠结/斑块相关。生化验证证实了 Notch1 在细胞质脑组分中的积累。蛋白质的增加并不伴随着 Notch1 靶标 Hes1 和 Hey1 的增加。对脑脊液 (CSF) 的检查表明，AD 患者中 Notch1 蛋白的全长和截短都减少了，这表明 Notch1 蛋白在脑实质中积累。我们的研究表明，Notch1 在散发性 AD 患者易感海马和皮质区域的纤维结构中显着移位和积累。 Notch1 在脑实质中的主要沉积及其在神经元中的总体信号减少在所有分析的 AD 患者中都是一致的，这表明 Notch1 可能被认为是 AD 的新标志。本文的在线版本 (doi:10.1186/s40478-016-0327-2) 包含补充材料，可供授权用户使用。
Notch1 signaling is a cellular cascade with a fundamental role from brain development to adult brain function. Reduction in Notch1 affects synaptic plasticity, memory and olfaction. On the other hand, Notch1 overactivation after brain injury is detrimental for neuronal survival. Some familial Alzheimer’s disease (FAD) mutations in Presenilins can affect Notch1 processing/activation. Others report that Notch1 is overexpressed in sporadic Alzheimer’s disease (AD). These works indicate that imbalances in Notch1 may be implicated in AD pathophysiology. In this study, we addressed whether Notch1 alteration can be considered a hallmark of AD. Immunohistochemical analysis of Notch1 on cortical and hippocampal tissue from post-mortem patients indicates an accumulation of Notch1 in plaque-like structures in the brain parenchyma of subjects with sporadic AD. Further analysis shows that displaced Notch1 is associated with fibrillary tangles/plaques. Biochemical validation confirms an accumulation of Notch1 in cytosolic brain fractions. This increase in protein is not accompanied with a raise in the Notch1 targets Hes1 and Hey1. Examination of the cerebrospinal fluid (CSF) indicates that the full length and truncations of the Notch1 protein are reduced in AD patients hinting at an accumulation in the brain parenchyma. Our research indicates that Notch1 is significantly displaced and accumulated in fibrillary structures in the susceptible hippocampal and cortical regions of sporadic AD patients. The dominant deposition of Notch1 in the brain parenchyma and its general signal reduction in neurons is consistent in all the AD patients analyzed and suggests that Notch1 may potentially be considered a novel hallmark of AD. The online version of this article (doi:10.1186/s40478-016-0327-2) contains supplementary material, which is available to authorized users.